This research proposal describes a five-year career development and training plan to prepare the candidate, Dr. Raiyan T. Zaman, for a career as an independent investigator. This program will build on Dr. Zaman's background as an Electrical and Biomedical Engineer with expertise in development of novel imaging system to investigate and characterize atherosclerotic vulnerable plaque. The primary Mentor is Dr. Michael V. McConnell who is a Professor of Cardiovascular Medicine of the Department of Medicine at the Stanford University School of Medicine. Also, co-Mentor Dr. Lei Xing is the Director of Radiation Physics Division of the Department of Radiation Oncology at the Stanford University School of Medicine. The proposed Mentors are expert in cardiovascular imaging, molecular imaging, and imaging reconstruction. The K99 phase will consist of structured mentorship by the mentors, complementary meeting with an advisory committee, a novel research project, and a program of career transition. In her preliminary studies, Dr. Zaman has developed a novel catheter based radionuclide optical imaging system in bench-top setting and validated the system in ex vivo murine atherosclerotic plaque. The system successfully detected atherosclerotic plaque by a novel scintillating balloon with a molecular probe, 18F-FDG. Dr. Zaman demonstrated vulnerable plaque inside carotid artery provided 4 higher radio-luminescence signal compared to control. To date the candidate has accrued the technical competencies necessary to conduct the proposed research on vulnerable plaque such as inflamed thin-cap fibro atheroma (TCFA), which is thought to account for 60% to 70% of coronary events. The overall goal of this project is to improve our understanding of atherosclerotic plaques characteristics and pathobiology within the coronary arteries. To address this overarching goal a novel intravascular dual-modality fiber-optic catheter radionuclide imaging (CRI) and 4D photoacoustic tomography (PAT) imaging system will be developed for molecular imaging of glucose uptake by metabolically active vulnerable plaque and gather information on plaque constituents. The current clinical paradigm for detecting CAD is angiography, which only evaluates the luminal encroachment of the disease, without providing information about plaque extent, content, and biology. Several study showed that 18F-FDG, a molecular probe, is considered to be a marker of metabolically active (vulnerable) plaques due to its uptake by inflammatory macrophages in the carotid and aorta. The major advantage of using 18F-FDG for vulnerable plaque detection is that it is FDA approved for cardiac and cancer imaging; thus, clinical transition may be more easily achieved. However, 18F-FDG detection in coronary plaque is still challenging due to their small size, motion, and obscuring signal by adjacent myocardium. These challenges have spurred the long-term goal of this research proposal to develop superior approaches to image coronary arterial inflammation and better define the TCFA constituents. In Specific Aim 1 during K99 phase, the novel dual-modality CRI-PAT imaging system will be built and the CRI and PAT part of the system will be tested separately on ex vivo aortic rabbit plaques (post IV injection of 18F-FDG) and postmortem human coronary plaques from autopsy specimens, respectively. These results will be correlated with histological and immunohistochemistry studies. In addition, these findings will be validated through IVIS-200 and autoradiography. A quantitative image map of the plaque constituents will be developed containing information on fatty acid, lipid or cholesterol, beta-carotene, elastin, collagen, and calcification. In the Specific Aim 2 during R00 phase, the candidate will use a comprehensive approach to test the system in in vivo rabbit aorta and will build data base on plaque constituents. In Specific Aim 3 during R00 phase, the CRI-PAT system will be used to evaluate the safety of the system in in vivo pig model as precursor to human testing. The evidence of injury and thrombosis will be assessed by autopsy. In addition, stable plaque, minimally inflamed fibrous lesion (created by balloon injury), will be compared to vulnerable plaque, inflamed thrombus lesion (created by copper stenting), by CRI-PAT. These results will be validated with autoradiography and histology/immunohistochemistry study. Dr. Zaman's ultimate goal is to use this information to characterize the vulnerable plaque by novel imaging modalities. Collectively, the proposed research work will elucidate novel imaging technology that will identify the vulnerable from stable plaque and characterize the vulnerable plaque with information on plaque constituents.